PROJECT SUMMARY It is estimated that approximately 50-60% of the general population will be exposed to at least one lifetime traumatic event. While most individuals recover from the experience, approximately 10-20% develop post- traumatic stress disorder (PTSD). We have recently found that, as in humans, approximately 25-35% of otherwise normal rats undergoing a stressful experience (e.g. footshocks) fail to extinguish conditioned fear responses. Such animals, which we refer to as ?weak-extinction? or ?extinction-deficient?, show increased anxiety-like responses and hypervigilance in behavioural tests. In patients with treatment-resistant depression and obsessive-compulsive disorder, promising results have been reported with the use of deep brain stimulation (DBS). To date, no study has been published investigating the outcome of DBS in PTSD. In pilot pre-clinical work, we have recently applied DBS to the infralimbic cortex (IL) of extinction-deficient rats and found that their behavioural deficits were completely reversed. Endocannabinoids (EC) are neuromodulatory lipids that play a major role in the control of fear and anxiety. EC receptors (CB1) are highly expressed in structures typically involved in neurocircuitry of stress and PTSD. In preclinical models, the systemic administration of CB1 EC receptors improves anxiety and extinction learning. Preliminary results from our laboratory suggest that systemic injections of drugs that inhibit the degradation of ECs (i.e. inhibitors of the enzyme fatty acid amide hydrolase; FAAH) counter behavioural deficits in weak- extinction rats. In addition, we found in a pilot study that the behavioural response of DBS in weak-extinction rats was completely blocked by the co-administration of cannabinoid receptor antagonists, suggesting that some DBS effects may be mediated by EC. The main hypotheses of our study are twofold: (i) Weak-extinction rats have a dysfunctional endocannabinoid system (e.g. increased levels/activity of EC catabolic enzymes), which may increase their susceptibility to develop fear/anxiety-like responses following stress. (ii) DBS improves extinction deficits and anxiety in weak- extinction rats via EC-mediated mechanisms. To test these hypotheses we will conduct different studies with two principal Aims: Aim 1: To demonstrate that chronic IL DBS improves fear and anxiety-like behavior in weak-extinction animals and ascertain potential biomarkers of a DBS response. Aim 2: To investigate whether extinction-deficient rats have pre-existing alterations in activity/levels of FAAH that may potentially lead them to develop abnormal behavioural responses following stress. To test the hypothesis that DBS-induced improvements in weak-extinction rats are mediated by the EC system. We anticipate that i) higher levels/activity of FAAH will be responsible for the extinction deficits and anxiety-like behaviour shown by weak extinction animals following fear conditioning, and ii) DBS will counter behavioural deficits in weak-extinction rats via EC-dependent mechanisms. This will be the first time endocannabinoids are implicated in the therapeutic effects of DBS. Besides providing important insight on how DBS works and helping to address potential mechanisms of fear/anxiety our findings may have indirect clinical relevance. The suffering and socioeconomic burden of PSTD is enormous. To date, not many therapeutic strategies are available for treatment-resistant patients. Though translation of data from animal models to humans always has to be considered with great caution, if successful, our study may pave the way for future investigation focusing on the development of a clinical trial to study the effects of DBS in treatment resistant PTSD